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Context: Hepatitis B virus (HBV) infection is one of the most prevalent public health problems worldwide (especially in developing countries). Aims: This study was carried out to determine the seroprevalence of HBV and its co-infection with hepatitis D (HDV) and C (HCV) viruses in the northeastern part of Iran. Setting and Design: A population-based cross-sectional study in Iran. Materials and Methods: As many as 1,850 subjects were explored for HBsAg. Anti-HDV and anti-HCV antibodies were assessed in HBsAg-positive cases. Statistical Analysis Used: Proportions were compared by Chi-square and Fisher′s exact tests. Results: The mean age of subjects was 43.86 ± 11.2 years. The age- and sex-standardized prevalence for HBsAg positivity was 9.7%. It was higher in males than in females (OR: 1.28; 95% CI: 0.9-1.7). The risk of infection in singles was significantly higher than in married cases (OR: 2.13). Eight (5.8%) of HBsAg-positive cases were infected with HDV, and 17 (12.3%) were positive for anti-HCV antibody. Conclusion: This study demonstrates that the prevalence of HBsAg seropositivity in Golestan province of Iran is higher than the levels reported by WHO and previous studies from Iran. It is very important, especially for health providers and policy makers, to recognize the risk factors of HBV infection and its co-infection with HDV and HCV in this area and design effective preventive programs.

Hepatitis delta virus (HDV) is a small, defective RNA virus that can infect only individuals who have hepatitis B virus (HBV); worldwide more than 15 million people are co-infected. There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity. The hepatitis D virion is composed of a coat of HBV envelope proteins surrounding the nucleocapsid, which consists of a single-stranded, circular RNA genome complexed with delta antigen, the viral protein. HDV is clinically important because although it suppresses HBV replication, it causes severe liver disease with rapid progression to cirrhosis and hepatic decompensation. The range of clinical presentation is wide, varying from mild disease to fulminant liver failure. The prevalence of HDV is declining in some endemic areas but increasing in northern and central Europe because of immigration. Treatment of HDV is with pegylated interferon alfa; however, response rates are poor. Increased understanding of the molecular virology of HDV will identify novel therapeutic targets for this most severe form of chronic viral hepatitis.

Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. Liver diseases related to the human hepatitis B virus (HBV) kill about 1 million people every year, and more than 350 million people around the world are infected with the virus. Some 15 million of these people are also infected with the hepatitis D virus (HDV), which is a satellite virus of HBV, and this places them at an even higher risk of liver diseases, including cancer. The viruses are known to enter liver cells by binding to receptors on their surface before being engulfed. Both HBV and HDV have outer coats that consist of three kinds of envelope proteins, and a region called the pre-S1 domain in one of them is known to have a central role in the interaction between the viruses and the receptors and, therefore, in infecting the cells. However, the identity of the HBV receptor has remained a mystery. Now Yan et al. have identified this receptor to be sodium taurocholate cotransporting polypeptide. This protein, known as NTCP for short, is normally involved in the circulation of bile acids in the body. In addition to humans, only two species are known to be susceptible to infection by human HBV and HDV—chimpanzees and a small mammal known as the treeshrew. Yan et al. started by isolating primary liver cells from treeshrews, and then used a combination of advanced purification and mass spectrometry analysis to show that the NTCP on the surface of the cells interacts with the pre-S1 domain in HBV. The authors then performed a series of gene knockdown experiments on liver cells of both human and treeshrew origin: when the gene that codes for NTCP was silenced, HBV infection was greatly reduced. Moreover, they were able to transfect HepG2 cells—which are widely used in research into liver disease, but are not susceptible to HBV and HDV infection—with NTCP from humans and treeshrews to make them susceptible. Similarly, although monkeys are not susceptible to HBV, replacing just five amino acids in monkey NTCP with their human counterparts was enough to make the monkey NTCP a functional receptor for the viruses. In the past, basic research into HBV and the development of antiviral therapeutics have both been hindered by the lack of suitable in vitro infection systems and animal models. Now, the work of Yan et al. means that it will be possible to use NTCP-complemented HepG2 cells for challenges as diverse as fundamental studies of basic viral entry/replication mechanisms and large-scale drug screening. It is also possible that HBV and HDV infection might interfere with some of the important physiological functions carried out by NTCP, so the latest work could also be of interest to medical scientists working on other diseases related to these infections.

Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.

Hepatitis D virus (HDV) depends on hepatitis B virus (HBV) to enter and exit hepatocytes and to replicate. Despite this dependency, HDV can cause severe liver disease. HDV accelerates liver fibrosis, increases the risk of hepatocellular carcinoma, and hastens hepatic decompensation compared to chronic HBV monoinfection. The Chronic Liver Disease Foundation (CLDF) formed an expert panel to publish updated guidelines on the testing, diagnosis, and management of hepatitis delta virus. The panel group performed network data review on the transmission, epidemiology, natural history, and disease sequelae of acute and chronic HDV infection. Based on current available evidence, we provide recommendations for screening, testing, diagnosis, and treatment of hepatitis D infection and review upcoming novel agents that may expand treatment options. The CLDF recommends universal HDV screening for all patients who are Hepatitis B surface antigen-positive. Initial screening should be with an assay to detect antibodies generated against HDV (anti-HDV). Patients who are positive for anti-HDV IgG antibodies should then undergo quantitative HDV RNA testing. We also provide an algorithm that describes CLDF recommendations on the screening, diagnosis, testing, and initial management of Hepatitis D infection.

Previous studies reported that the hepatitis C virus (HCV) could help disseminate the hepatitis D virus (HDV) in vivo through the unrelated hepatitis B virus (HBV), but with essentially inconclusive results. To try to shed light on this still-debated topic, 146 anti-HCV-positive subjects (of whom 91 HCV/HIV co-infected, and 43 with prior HCV eradication) were screened for anti-HDV antibodies (anti-HD), after careful selection for negativity to any serologic or virologic marker of current or past HBV infection. One single HCV/HIV co-infected patient (0.7%) tested highly positive for anti-HD, but with no positive HDV-RNA. Her husband, in turn, was a HCV/HIV co-infected subject with a previous contact with HBV. While conducting a thorough review of the relevant literature, the authors attempted to exhaustively describe the medical history of both the anti-HD-positive patient and her partner, believing it to be the key to dissecting the possible complex mechanisms of HDV transmission from one subject to another, and speculating that in the present case, it may have been HCV itself that behaved as an HDV helper virus. In conclusion, this preliminary research, while needing further validation in large prospective studies, provided some further evidence of a role of HCV in HDV dissemination in humans.

The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of HBV, HDV requires the surface antigen of HBV (HBsAg) for sufficient viral packaging and spread. The special circumstance of co-infection, albeit only one partner depends on the other, raises many virological, immunological, and pathophysiological questions. In the last years, breakthroughs were made in understanding the adaptive immune response, in particular, virus-specific CD4+ and CD8+ T cells, in self-limited versus persistent HBV/HDV co-infection. Indeed, the mechanisms of CD8+ T cell failure in persistent HBV/HDV co-infection include viral escape and T cell exhaustion, and mimic those in other persistent human viral infections, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), and HBV mono-infection. However, compared to these larger viruses, the small HDV has perfectly adapted to evade recognition by CD8+ T cells restricted by common human leukocyte antigen (HLA) class I alleles. Furthermore, accelerated progression towards liver cirrhosis in persistent HBV/HDV co-infection was attributed to an increased immune-mediated pathology, either caused by innate pathways initiated by the interferon (IFN) system or triggered by misguided and dysfunctional T cells. These new insights into HDV-specific adaptive immunity will be discussed in this review and put into context with known well-described aspects in HBV, HCV, and HIV infections.

Hepatitis D is the most severe viral hepatitis. Hepatitis D virus (HDV) has a very small RNA genome with unique biological properties. It requires for infection the presence of hepatitis B virus (HBV) and is transmitted parenterally, mainly by superinfection of HBsAg carriers who then develop chronic hepatitis D. HDV has been brought under control in high-income countries by the implementation of HBV vaccination, and the clinical pattern has changed to a chronic hepatitis D seen in ageing patients with advanced fibrotic disease; the disease remains a major health concern in developing countries of Africa and Asia. Every HBsAg-positive subject should be tested for HDV serum markers by reflex testing, independently of clinical status. Vaccination against HBV provides the best prophylaxis against hepatitis D. The only therapy available so far has been the poorly performing Interferon alfa; however, several new and promising therapeutic approaches are under study.

Background. Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis of other liver diseases. Methods. NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied. Results. Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis. Conclusion. NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors.